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1.
Genes (Basel) ; 11(11)2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33202925

RESUMO

The association between a common PRSS1-PRSS2 haplotype and alcoholic chronic pancreatitis (ACP), which was revealed by the first genome-wide association study of chronic pancreatitis (CP), has been consistently replicated. However, the association with non-ACP (NACP) has been controversial. Herein, we sought to clarify this basic issue by means of an allele-based meta-analysis of currently available studies. We then used studies informative for genotype distribution to explore the biological mechanisms underlying the association data and to test for gene-environment interaction between the risk haplotype and alcohol consumption by means of a re-analysis. A literature search was conducted to identify eligible studies. A meta-analysis was performed using the Review Manager software. The association between the risk genotypes and NACP or ACP was tested for the best-fitting genetic model. Gene-environment interaction was estimated by both case-only and multinomial approaches. Five and eight studies were employed for the meta-analysis of ACP and NACP findings, respectively. The risk allele was significantly associated with both ACP (pooled odds ratio (OR) 1.67, 95% confidence interval (CI) 1.56-1.78; p < 0.00001) and NACP (pooled OR 1.28, 95% CI 1.17-1.40; p < 0.00001). Consistent with a dosage effect of the risk allele on PRSS1/PRSS2 mRNA expression in human pancreatic tissue, both ACP and NACP association data were best explained by an additive genetic model. Finally, the risk haplotype was found to interact synergistically with alcohol consumption.

2.
Nat Commun ; 11(1): 5918, 2020 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-33219223

RESUMO

Identifying pathogenic variants and underlying functional alterations is challenging. To this end, we introduce MutPred2, a tool that improves the prioritization of pathogenic amino acid substitutions over existing methods, generates molecular mechanisms potentially causative of disease, and returns interpretable pathogenicity score distributions on individual genomes. Whilst its prioritization performance is state-of-the-art, a distinguishing feature of MutPred2 is the probabilistic modeling of variant impact on specific aspects of protein structure and function that can serve to guide experimental studies of phenotype-altering variants. We demonstrate the utility of MutPred2 in the identification of the structural and functional mutational signatures relevant to Mendelian disorders and the prioritization of de novo mutations associated with complex neurodevelopmental disorders. We then experimentally validate the functional impact of several variants identified in patients with such disorders. We argue that mechanism-driven studies of human inherited disease have the potential to significantly accelerate the discovery of clinically actionable variants.

3.
Cell Rep ; 33(4): 108308, 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33113372

RESUMO

Identifying the molecular programs underlying human organ development and how they differ from model species is key for understanding human health and disease. Developmental gene expression profiles provide a window into the genes underlying organ development and a direct means to compare them across species. We use a transcriptomic resource covering the development of seven organs to characterize the temporal profiles of human genes associated with distinct disease classes and to determine, for each human gene, the similarity of its spatiotemporal expression with its orthologs in rhesus macaque, mouse, rat, and rabbit. We find clear associations between spatiotemporal profiles and the phenotypic manifestations of diseases. We also find that half of human genes differ from their mouse orthologs in their temporal trajectories in at least one of the organs. These include more than 200 genes associated with brain, heart, and liver disease for which mouse models should undergo extra scrutiny.

4.
Transfusion ; 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32757236

RESUMO

BACKGROUND: Thrombocytopenia has a variety of different etiologies, both acquired and hereditary. Inherited thrombocytopenia may be associated with other symptoms (syndromic forms) or may be strictly isolated. To date, only about half of all the familial forms of thrombocytopenia have been accounted for in terms of well-defined genetic abnormalities. However, data are limited on the nature and frequency of the underlying causative genetic variants in individuals with mild isolated nonsyndromic thrombocytopenia. STUDY DESIGN AND METHODS: Thirteen known or candidate genes for isolated thrombocytopenia were included in a gene panel analysis in which targeted next-generation sequencing was performed on 448 French blood donors with mild isolated nonsyndromic thrombocytopenia. RESULTS: A total of 68 rare variants, including missense, splice site, frameshift, nonsense, and in-frame variants (all heterozygous) were identified in 11 of the 13 genes screened. Twenty-nine percent (N = 20) of the variants detected were absent from both the French Exome Project and gnomAD exome databases. Using stringent criteria and an unbiased approach, we classified seven predicted loss-of-function variants (three in ITGA2B and four in TUBB1) and four missense variants (one in GP1BA, two in ITGB3 and one in ACTN1) as being pathogenic or likely pathogenic. Altogether, they were found in 13 members (approx. 3%) of our studied cohort. CONCLUSION: We present the results of gene panel sequencing of known and candidate thrombocytopenia genes in mild isolated nonsyndromic thrombocytopenia. Pathogenic and likely pathogenic variants in five known thrombocytopenia genes were identified, accounting for approximately 3% of individuals with the condition.

5.
J Clin Lipidol ; 14(4): 498-506, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32561169

RESUMO

BACKGROUND: The etiology of hypertriglyceridemia (HTG) and, consequently, HTG-induced acute pancreatitis (HTG-AP), is complex. OBJECTIVE: Herein, we explore a possible gene-environment interaction between APOA5 c.553G>T (p.185Gly>Cys, rs2075291), a common variant associated with altered triglyceride levels, and pregnancy in HTG-AP. METHODS: We enrolled 318 Chinese HTG-AP patients and divided them into 3 distinct groups: Group 1, male patients (n = 183); Group 2, female patients whose disease was unrelated to pregnancy (n = 105); and Group 3, female patients whose disease was related to pregnancy (n = 30). APOA5 rs2075291 genotype status was determined by Sanger sequencing. A total of 362 healthy Han Chinese subjects were used as controls. Data on body mass index, peak triglyceride level, age of disease onset, episode number, and clinical severity of HTG-AP were collected from each patient. Multiple comparisons, between patient groups, between patient groups and controls, or within each patient group, were performed. RESULTS: A robust association of APOA5 rs2075291 with HTG-AP in general, and HTG-AP during pregnancy in particular, was demonstrated. The minor T allele showed a stronger association with Group 3 patients than with either Group 1 or Group 2 patients. This stronger association was due mainly to the much higher frequency of TT genotype in Group 3 patients (20%) than that (<6%) in Group 1 and Group 2 patients. Moreover, the TT genotype was associated with a significantly higher peak triglyceride level in Group 3 patients compared with the GG genotype. CONCLUSION: Our findings provide evidence for an interaction between APOA5 rs2075291 and pregnancy in HTG-AP.

6.
Proc Natl Acad Sci U S A ; 117(24): 13626-13636, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32487729

RESUMO

Humans homozygous or hemizygous for variants predicted to cause a loss of function (LoF) of the corresponding protein do not necessarily present with overt clinical phenotypes. We report here 190 autosomal genes with 207 predicted LoF variants, for which the frequency of homozygous individuals exceeds 1% in at least one human population from five major ancestry groups. No such genes were identified on the X and Y chromosomes. Manual curation revealed that 28 variants (15%) had been misannotated as LoF. Of the 179 remaining variants in 166 genes, only 11 alleles in 11 genes had previously been confirmed experimentally to be LoF. The set of 166 dispensable genes was enriched in olfactory receptor genes (41 genes). The 41 dispensable olfactory receptor genes displayed a relaxation of selective constraints similar to that observed for other olfactory receptor genes. The 125 dispensable nonolfactory receptor genes also displayed a relaxation of selective constraints consistent with greater redundancy. Sixty-two of these 125 genes were found to be dispensable in at least three human populations, suggesting possible evolution toward pseudogenes. Of the 179 LoF variants, 68 could be tested for two neutrality statistics, and 8 displayed robust signals of positive selection. These latter variants included a known FUT2 variant that confers resistance to intestinal viruses, and an APOL3 variant involved in resistance to parasitic infections. Overall, the identification of 166 genes for which a sizeable proportion of humans are homozygous for predicted LoF alleles reveals both redundancies and advantages of such deficiencies for human survival.


Assuntos
Genética Humana , Mutação com Perda de Função , Alelos , Apolipoproteínas L/genética , Fucosiltransferases/genética , Variação Genética , Homozigoto , Humanos , Proteínas/genética , Cromossomos Sexuais/genética
7.
Hum Genet ; 139(10): 1197-1207, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32596782

RESUMO

The Human Gene Mutation Database (HGMD®) constitutes a comprehensive collection of published germline mutations in nuclear genes that are thought to underlie, or are closely associated with human inherited disease. At the time of writing (June 2020), the database contains in excess of 289,000 different gene lesions identified in over 11,100 genes manually curated from 72,987 articles published in over 3100 peer-reviewed journals. There are primarily two main groups of users who utilise HGMD on a regular basis; research scientists and clinical diagnosticians. This review aims to highlight how to make the most out of HGMD data in each setting.


Assuntos
Bases de Dados Genéticas , Genoma Humano , Mutação em Linhagem Germinativa , Polimorfismo Genético , Bibliometria , Pesquisa Biomédica/métodos , Predisposição Genética para Doença , Humanos , Parcerias Público-Privadas
8.
Hum Mutat ; 41(8): 1358-1364, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32369867

RESUMO

In the human genome, most 5' splice sites (~99%) employ the canonical GT dinucleotide whereas a small minority (~1%) use the noncanonical GC dinucleotide. The functionality and pathogenicity of 5' splice site GT>GC (+2T>C) variants have been extensively studied but we know very little about 5' splice site GC>GT (+2C>T) variants. Herein, we have addressed this deficiency by performing a meta-analysis of reported +2C>T "pathogenic" variants together with a functional analysis of engineered +2C>T substitutions using a cell culture-based full-length gene splicing assay. Our results establish proof of concept that +2C>T variants are qualitatively different from +2T>C variants in terms of their functionality and suggest that, in sharp contrast to +2T>C variants, most if not all +2C>T variants have no pathological relevance. Our findings have important implications for interpreting the clinical relevance of +2C>T variants and understanding the evolutionary switching between GT and GC 5' splice sites in mammalian genomes.

9.
Sci Transl Med ; 12(544)2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32434849

RESUMO

The diagnosis of Mendelian disorders requires labor-intensive literature research. Trained clinicians can spend hours looking for the right publication(s) supporting a single gene that best explains a patient's disease. AMELIE (Automatic Mendelian Literature Evaluation) greatly accelerates this process. AMELIE parses all 29 million PubMed abstracts and downloads and further parses hundreds of thousands of full-text articles in search of information supporting the causality and associated phenotypes of most published genetic variants. AMELIE then prioritizes patient candidate variants for their likelihood of explaining any patient's given set of phenotypes. Diagnosis of singleton patients (without relatives' exomes) is the most time-consuming scenario, and AMELIE ranked the causative gene at the very top for 66% of 215 diagnosed singleton Mendelian patients from the Deciphering Developmental Disorders project. Evaluating only the top 11 AMELIE-scored genes of 127 (median) candidate genes per patient resulted in a rapid diagnosis in more than 90% of cases. AMELIE-based evaluation of all cases was 3 to 19 times more efficient than hand-curated database-based approaches. We replicated these results on a retrospective cohort of clinical cases from Stanford Children's Health and the Manton Center for Orphan Disease Research. An analysis web portal with our most recent update, programmatic interface, and code is available at AMELIE.stanford.edu.

10.
Mol Genet Genomic Med ; 8(3): e1048, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31962008

RESUMO

BACKGROUND: Acute pancreatitis in pregnancy (APIP) is a life-threatening disease for both mother and fetus. To date, only three patients with recurrent hypertriglyceridemia-induced APIP (HTG-APIP) have been reported to carry rare variants in the lipoprotein lipase (LPL) gene, which encodes the key enzyme responsible for triglyceride (TG) metabolism. Coincidently, all three patients harbored LPL variants on both alleles and presented with complete or severe LPL deficiency. METHODS: The entire coding regions and splice junctions of LPL and four other TG metabolism genes (APOC2, APOA5, GPIHBP1, and LMF1) were analyzed by Sanger sequencing in a Han Chinese patient who had experienced two episodes of HTG-APIP. The impact of a novel LPL missense variant on LPL protein expression and activity was analyzed by transient expression in HEK293T cells. RESULTS: A novel heterozygous LPL missense variant, p.His210Leu (c.629A > T), was identified in our patient. This variant did not affect protein synthesis but significantly impaired LPL secretion and completely abolished the enzymatic activity of the mutant protein. CONCLUSION: This report describes the first identification and functional characterization of a heterozygous variant in the LPL that predisposed to recurrent HTG-APIP. Our findings confirm a major genetic contribution to the etiology of individual predisposition to HTG-APIP.

11.
Genet Med ; 22(2): 362-370, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31467448

RESUMO

PURPOSE: Both monogenic pathogenic variant cataloging and clinical patient diagnosis start with variant-level evidence retrieval followed by expert evidence integration in search of diagnostic variants and genes. Here, we try to accelerate pathogenic variant evidence retrieval by an automatic approach. METHODS: Automatic VAriant evidence DAtabase (AVADA) is a novel machine learning tool that uses natural language processing to automatically identify pathogenic genetic variant evidence in full-text primary literature about monogenic disease and convert it to genomic coordinates. RESULTS: AVADA automatically retrieved almost 60% of likely disease-causing variants deposited in the Human Gene Mutation Database (HGMD), a 4.4-fold improvement over the current best open source automated variant extractor. AVADA contains over 60,000 likely disease-causing variants that are in HGMD but not in ClinVar. AVADA also highlights the challenges of automated variant mapping and pathogenicity curation. However, when combined with manual validation, on 245 diagnosed patients, AVADA provides valuable evidence for an additional 18 diagnostic variants, on top of ClinVar's 21, versus only 2 using the best current automated approach. CONCLUSION: AVADA advances automated retrieval of pathogenic monogenic variant evidence from full-text literature. Far from perfect, but much faster than PubMed/Google Scholar search, careful curation of AVADA-retrieved evidence can aid both database curation and patient diagnosis.

13.
Zool Res ; 41(1): 3-19, 2020 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-31840949

RESUMO

Hypobaric hypoxia (HH) exposure can cause serious brain injury as well as life-threatening cerebral edema in severe cases. Previous studies on the mechanisms of HH-induced brain injury have been conducted primarily using non-primate animal models that are genetically distant to humans, thus hindering the development of disease treatment. Here, we report that cynomolgus monkeys ( Macaca fascicularis) exposed to acute HH developed human-like HH syndrome involving severe brain injury and abnormal behavior. Transcriptome profiling of white blood cells and brain tissue from monkeys exposed to increasing altitude revealed the central role of the HIF-1 and other novel signaling pathways, such as the vitamin D receptor (VDR) signaling pathway, in co-regulating HH-induced inflammation processes. We also observed profound transcriptomic alterations in brains after exposure to acute HH, including the activation of angiogenesis and impairment of aerobic respiration and protein folding processes, which likely underlie the pathological effects of HH-induced brain injury. Administration of progesterone (PROG) and steroid neuroprotectant 5α-androst-3ß,5,6ß-triol (TRIOL) significantly attenuated brain injuries and rescued the transcriptomic changes induced by acute HH. Functional investigation of the affected genes suggested that these two neuroprotectants protect the brain by targeting different pathways, with PROG enhancing erythropoiesis and TRIOL suppressing glutamate-induced excitotoxicity. Thus, this study advances our understanding of the pathology induced by acute HH and provides potential compounds for the development of neuroprotectant drugs for therapeutic treatment.


Assuntos
Androstanóis/farmacologia , Hipóxia/veterinária , Macaca fascicularis , Doenças dos Macacos/prevenção & controle , Progesterona/farmacologia , Transcriptoma , Androstanóis/administração & dosagem , Animais , Encefalopatias/prevenção & controle , Encefalopatias/veterinária , Cálcio/metabolismo , Regulação da Expressão Gênica , Hipóxia/patologia , Leucócitos/metabolismo , Masculino , Fármacos Neuroprotetores/farmacologia , Pressão , Progesterona/administração & dosagem
14.
Genome Biol ; 20(1): 254, 2019 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-31779641

RESUMO

Single nucleotide variants (SNVs) in intronic regions have yet to be systematically investigated for their disease-causing potential. Using known pathogenic and neutral intronic SNVs (iSNVs) as training data, we develop the RegSNPs-intron algorithm based on a random forest classifier that integrates RNA splicing, protein structure, and evolutionary conservation features. RegSNPs-intron showed excellent performance in evaluating the pathogenic impacts of iSNVs. Using a high-throughput functional reporter assay called ASSET-seq (ASsay for Splicing using ExonTrap and sequencing), we evaluate the impact of RegSNPs-intron predictions on splicing outcome. Together, RegSNPs-intron and ASSET-seq enable effective prioritization of iSNVs for disease pathogenesis.


Assuntos
Doença/genética , Técnicas Genéticas , Íntrons , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Algoritmos , Processamento Alternativo , Éxons , Frequência do Gene , Humanos , Software
15.
Cell ; 179(4): 984-1002.e36, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31675503

RESUMO

Genomic studies in African populations provide unique opportunities to understand disease etiology, human diversity, and population history. In the largest study of its kind, comprising genome-wide data from 6,400 individuals and whole-genome sequences from 1,978 individuals from rural Uganda, we find evidence of geographically correlated fine-scale population substructure. Historically, the ancestry of modern Ugandans was best represented by a mixture of ancient East African pastoralists. We demonstrate the value of the largest sequence panel from Africa to date as an imputation resource. Examining 34 cardiometabolic traits, we show systematic differences in trait heritability between European and African populations, probably reflecting the differential impact of genes and environment. In a multi-trait pan-African GWAS of up to 14,126 individuals, we identify novel loci associated with anthropometric, hematological, lipid, and glycemic traits. We find that several functionally important signals are driven by Africa-specific variants, highlighting the value of studying diverse populations across the region.

16.
Front Genet ; 10: 835, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31572445

RESUMO

Polyhydramnios is sometimes associated with genetic defects. However, establishing an accurate diagnosis and pinpointing the precise genetic cause of polyhydramnios in any given case represents a major challenge because it is known to occur in association with over 200 different conditions. Whole exome sequencing (WES) is now a routine part of the clinical workup, particularly with diseases characterized by atypical manifestations and significant genetic heterogeneity. Here we describe the identification, by means of WES, of novel compound heterozygous truncating variants in the LMOD3 gene [i.e., c.1412delA (p.Lys471Serfs*18) and c.1283dupC (p.Gly429Trpfs*35)] in a Chinese family with two successive fetuses affected with polyhydramnios, thereby potentiating the prenatal diagnosis of nemaline myopathy (NM) in the proband. LMOD3 encodes leiomodin-3, which is localized to the pointed ends of thin filaments and acts as a catalyst of actin nucleation in skeletal and cardiac muscle. This is the first study to describe the prenatal and postnatal manifestations of LMOD3-related NM in the Chinese population. Of all the currently reported NM-causing LMOD3 nonsense and frameshifting variants, c.1412delA generates the shortest truncation at the C-terminal end of the protein, underscoring the critical role of the WH2 domain in LMOD3 structure and function. Survey of the prenatal phenotypes of all known LMOD3-related severe NM cases served to identify fetal edema as a novel presenting feature that may provide an early clue to facilitate prenatal diagnosis of the disease.

17.
Nat Commun ; 10(1): 4141, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31515488

RESUMO

Each human genome carries tens of thousands of coding variants. The extent to which this variation is functional and the mechanisms by which they exert their influence remains largely unexplored. To address this gap, we leverage the ExAC database of 60,706 human exomes to investigate experimentally the impact of 2009 missense single nucleotide variants (SNVs) across 2185 protein-protein interactions, generating interaction profiles for 4797 SNV-interaction pairs, of which 421 SNVs segregate at > 1% allele frequency in human populations. We find that interaction-disruptive SNVs are prevalent at both rare and common allele frequencies. Furthermore, these results suggest that 10.5% of missense variants carried per individual are disruptive, a higher proportion than previously reported; this indicates that each individual's genetic makeup may be significantly more complex than expected. Finally, we demonstrate that candidate disease-associated mutations can be identified through shared interaction perturbations between variants of interest and known disease mutations.


Assuntos
Frequência do Gene/genética , Variação Genética , Genética Populacional , Alelos , Animais , Sequência de Bases , Doença/genética , Predisposição Genética para Doença , Genoma Humano , Células HEK293 , Humanos , Camundongos , Mutação de Sentido Incorreto/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Ligação Proteica/genética
18.
Front Pharmacol ; 10: 830, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31427963

RESUMO

Background: The incorporation of genomic testing into clinical practice constitutes an opportunity to improve patients' lives, as it makes possible the implementation of innovative, individualized clinical interventions that maximize efficacy and/or minimize the risk of adverse drug reactions. In order to ensure equal access to genomic testing for all patients, the costs associated with these tests should be reimbursed by their respective national healthcare systems. Given that funding for the public health sector is decreasing in real terms, it is of paramount importance that the emerging interventions are thoroughly evaluated both in terms of their clinical effectiveness and their full economic cost. Objective: The aim of this study was to identify those genome-guided interventions that could be adopted and reimbursed by national healthcare systems. Further, we recorded the underlying factors determining the broad adoption of genome-guided interventions in clinical practice, in order to identify potential reimbursement criteria. Methods: We performed a systematic review of published (PubMed-listed) scientific articles on the economic evaluation of those individualized clinical interventions that include genomic tests. Information on genomic tests reimbursed by the US Medicare program was also included. Subsequently, we correlated the regulatory guidance given for the interventions collated in our systematic review with the corresponding economic evaluation results and policies of the Medicare program. Regulatory guidance information was collected from the PharmGKB online knowledgebase and the Clinical Pharmacogenetics Implementation Consortium (CPIC). Results: Most of the included studies constitute cost-utility analyses, in which the outcome of the interventions has been measured in quality-adjusted life years (QALYs) whereas an estimate of the total cost has been based upon direct medical cost data. Favorable economic evaluation results, as well as concrete evidence demonstrating the clinical utility of pre-emptive genotyping, are considered as prerequisites for the broad adoption and reimbursement of the costs incurred during genomic testing. Indicatively, pre-emptive HLA-B*5701 and TPMT testing before administration of abacavir and azathioprine, respectively, is reimbursed by Medicare based on both economic and efficacy evidence. Likewise, the medical necessary screening for MMR and BRCA1/2 genes are reimbursed for high-risk populations. Conclusions: Our findings further underline the need for further cost-utility analyses within different national healthcare systems, in order to promote the reimbursement of the cost of innovative genome-guided therapeutic interventions.

19.
Nature ; 571(7766): 505-509, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31243369

RESUMO

The evolution of gene expression in mammalian organ development remains largely uncharacterized. Here we report the transcriptomes of seven organs (cerebrum, cerebellum, heart, kidney, liver, ovary and testis) across developmental time points from early organogenesis to adulthood for human, rhesus macaque, mouse, rat, rabbit, opossum and chicken. Comparisons of gene expression patterns identified correspondences of developmental stages across species, and differences in the timing of key events during the development of the gonads. We found that the breadth of gene expression and the extent of purifying selection gradually decrease during development, whereas the amount of positive selection and expression of new genes increase. We identified differences in the temporal trajectories of expression of individual genes across species, with brain tissues showing the smallest percentage of trajectory changes, and the liver and testis showing the largest. Our work provides a resource of developmental transcriptomes of seven organs across seven species, and comparative analyses that characterize the development and evolution of mammalian organs.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Organogênese/genética , Transcriptoma/genética , Animais , Evolução Biológica , Galinhas/genética , Feminino , Humanos , Macaca mulatta/genética , Masculino , Camundongos , Gambás/genética , Coelhos , Ratos
20.
PLoS Comput Biol ; 15(6): e1007112, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31199787

RESUMO

Differentiation between phenotypically neutral and disease-causing genetic variation remains an open and relevant problem. Among different types of variation, non-frameshifting insertions and deletions (indels) represent an understudied group with widespread phenotypic consequences. To address this challenge, we present a machine learning method, MutPred-Indel, that predicts pathogenicity and identifies types of functional residues impacted by non-frameshifting insertion/deletion variation. The model shows good predictive performance as well as the ability to identify impacted structural and functional residues including secondary structure, intrinsic disorder, metal and macromolecular binding, post-translational modifications, allosteric sites, and catalytic residues. We identify structural and functional mechanisms impacted preferentially by germline variation from the Human Gene Mutation Database, recurrent somatic variation from COSMIC in the context of different cancers, as well as de novo variants from families with autism spectrum disorder. Further, the distributions of pathogenicity prediction scores generated by MutPred-Indel are shown to differentiate highly recurrent from non-recurrent somatic variation. Collectively, we present a framework to facilitate the interrogation of both pathogenicity and the functional effects of non-frameshifting insertion/deletion variants. The MutPred-Indel webserver is available at http://mutpred.mutdb.org/.


Assuntos
Predisposição Genética para Doença/genética , Genoma Humano , Mutação INDEL , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/fisiopatologia , Biologia Computacional , Bases de Dados Genéticas , Genoma Humano/genética , Genoma Humano/fisiologia , Humanos , Mutação INDEL/genética , Mutação INDEL/fisiologia , Aprendizado de Máquina , Curva ROC
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